Mitochondrial Genetics Research Group
Research Group Head
Mitochondrial DNA is very important for the generation of cellular energy. We inherit our mitochondrial DNA from our mothers. Mutations to mitochondrial DNA and low levels of mitochondrial DNA copy number can lead to severe metabolic disorders.
The overall aim of Professor St. John’s team’s research is to understand how mitochondrial DNA is replicated, transmitted and segregated during development so that cells, tissues and organs function efficiently. The team is applying this knowledge to develop new reproductive strategies to help women who suffer from repeated failed fertilisation outcome or embryo developmental arrest; and enhanced genetics for animal breeding purposes.
Mapping mitochondrial DNA during development
Professor St. John and his team have mapped the patterns of replication and transmission as mitochondrial DNA passes from the fertilised oocyte into preimplantation embryos, fetuses and live offspring. They have also studied these events following nuclear transfer (cloning) and shown that mitochondrial DNA accompanying the donor cell is transmitted at highly variable levels due to the premature expression of the mitochondrial DNA specific replication factors. By depleting donor cell mitochondrial DNA prior to nuclear transfer, they have generated live offspring that inherit their mitochondrial DNA from the oocyte only, as is the case following natural conception. These outcomes have commercial applications in animal breeding programs to derive new lines of livestock.
Mapping of mitochondrial DNA in embryonic stem cells
To provide a more focussed molecular analysis during lineage specific differentiation, the team has mapped mitochondrial DNA replication events in pluripotent and differentiating embryonic stem cells. This has enabled them to identify a relationship between mitochondrial DNA copy number and pluripotency and that differentiation involves changes in mitochondrial DNA copy number and expression of the mitochondrial DNA-specific replication factors. From this baseline, the team has observed subtle differences in somatic cells reprogrammed to be ‘stem cell-like’ due to alternate patterns of mitochondrial DNA replication, which can account for their failure to differentiate. These outcomes have now enabled the team to understand how cancer stem cells regulate their mitochondrial DNA copy number and why certain cancer cells cannot differentiate.
Strategies for preventing the transmission of mutant mitochondrial DNA
Professor St. John’s team is working to apply knowledge from the replication of mitochondrial DNA during development to develop strategies to help women who suffer from repeated failed fertilisation outcome and embryo arrest. He has developed mitochondrial DNA supplementation protocols that result in increased fertilisation outcome and enhanced embryo quality and discovered the mechanism that regulates this process.
Kelly RD, Mahmud A, McKenzie M, Trounce IA, St. John JC. Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A. Nucleic Acids Research 2012; 40:10124-38.
Dickinson A, Yeung KY, Donoghue J, Baker MJ, Kelly RDW, McKenzie M, Johns TG, St. John JC. The regulation of mitochondrial DNA copy number in Glioblastoma cells. Cell Death & Differentiation 2013; 20; 1644-1653.
Kelly RDW, Rodda AE, Dickinson A, Mahmud A, Nefzger CM, Lee W, Forsythe JS, Polo JM, Trounce IA, McKenzie M, Nisbet DR, St. John JC. Mitochondrial DNA haplotypes define gene expression patterns in pluripotent and differentiating embryonic stem cells. Stem Cells 2013; 31:703-16.
Lee W, Johnson J, Gough DJ, Donoghue J, Cagnone GLM, Vaghijani V, Brown KA, Johns TG, St. John JC. Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny. Cell Death & Disease 2015; 6 (2):e1664.
Cagnone GLM, Tsai T-S, Makanji Y, Matthews P, Gould J, Bonkowski MS, Elgass KD, Wong ASA, Wu LE, McKenzie M, Sinclair DA, St. John JC. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. Scientific Reports 2016; 6: 23229.